Although different reprogramming systems may use different routes to achieve reprogramming, we think that five steps are required for the complete switch from a differentiated somatic cell to an embryonic cell or to an unrelated differentiated cell by nuclear transfer, cell fusion or induced pluripotency (Box 1). In the case of nuclear transfer to second meiotic metaphase eggs and induced pluripotency by transcription factor overexpression, all five steps take place in an overlapping time sequence. By contrast, these reprogramming steps seem to be separate in nuclear transfer to Xenopus oocyte (first meiotic prophase) experiments in which only steps i–iii take place. Cell division (step iv) and suppression of competing pathways (step v) occur only as eggs divide and as different cell lineages begin to appear. However, resistance to reprogramming is clearly evident in oocyte nuclear transfer experiments in the absence of cell division. We conclude that resistance to reprogramming in nuclear transfer experiments is caused, at least in part, by incomplete chromatin decondensation, incomplete removal of differentiation chromatin marks and, hence, by incomplete transcriptional activation. As cells differentiate, they progressively
